8DD2

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus Zolpidem

Summary for 8DD2

• Entry DOI: 10.2210/pdb8dd2/pdb
• EMDB information: 27332 27333
• Descriptor: Gamma-aminobutyric acid receptor subunit beta-2, Zolpidem, GAMMA-AMINO-BUTANOIC ACID, ... (11 entities in total)
• Functional Keywords: gabaa receptor, zolpidem, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 365526.06

Authors

Zhu, S.,Hibbs, R.E. (deposition date: 2022-06-17, release date: 2022-08-17, Last modification date: 2023-11-15)

Primary citation

Zhu, S.,Sridhar, A.,Teng, J.,Howard, R.J.,Lindahl, E.,Hibbs, R.E.
Structural and dynamic mechanisms of GABA A receptor modulators with opposing activities.
Nat Commun, 13:4582-4582, 2022

PubMed Abstract: γ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the α/γ subunit interface and two transmembrane sites at β/α interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA receptor allosteric modulators acting through a common site can have diverging activities.

PubMed: 35933426
DOI: 10.1038/s41467-022-32212-4

Experimental method

ELECTRON MICROSCOPY (2.9 Å)